The long-term objective of these studies is to understand how retroviruses that do not possess oncogenes are able to cause neoplastic diseases. These neoplasias typically occur in multiple stages involving long latency periods similar to most human cancers. The early events that are critical for the development of tumors are especially difficult to study. The murine leukemia viruses (MLVs) provide an ideal model system to identify these early events because they have a well-delineated preleukemic period. In our studies of the early stages of thymic lymphoma development in mice, we demonstrated that infection by a mink cell focus-forming (MCF) MLV led to an enhancement of apoptosis of thymic lymphocytes. Recent in vitro studies have shown that virus infection can directly induce apoptosis in certain cells. To better understand the role of apoptosis in tumorigenesis by MCF13 MLV, we propose to elucidate the mechanism by which this process occurs.
Aim 1 examines the requirement for apoptosis in MCF MLV-induced lymphomagenesis. MLVs with different pathogenic and cytopathic properties will be compared in in vitro and in vivo studies. The role of antiapoptotic proteins in rescuing virus-infected cells from apoptosis will be defined.
Aim 2 elucidates the mechanism by which glycoprotein binding to the MCF MLV receptor (XPR1) induces apoptosis. Immunoadhesins comprised of the MCF glycoprotein will be employed. Identification of the apoptotic signaling pathway involved in glycoprotein-receptor interactions will be made.
Aim 3 focuses on the role of receptor polymorphism in virus-mediated cell killing. XPR1 proteins cloned from different animals will be tested for their ability to mediate cell killing. Hybrid receptor proteins will be made to identify the regions of XPR1 that are essential for cytopathicity. The results of these studies will enhance our understanding of the role of apoptosis in the development of neoplastic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044166-17
Application #
6701309
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Cole, John S
Project Start
1979-04-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
17
Fiscal Year
2004
Total Cost
$279,319
Indirect Cost
Name
Wayne State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Yoshimura, Fayth K; Luo, Xixia; Zhao, Xiaoqing et al. (2008) Up-regulation of a cellular protein at the translational level by a retrovirus. Proc Natl Acad Sci U S A 105:5543-8
Zhao, Xiaoqing; Yoshimura, Fayth K (2008) Expression of murine leukemia virus envelope protein is sufficient for the induction of apoptosis. J Virol 82:2586-9
Yoshimura, Fayth K; Luo, Xixia (2007) Induction of endoplasmic reticulum stress in thymic lymphocytes by the envelope precursor polyprotein of a murine leukemia virus during the preleukemic period. J Virol 81:4374-7
Nanua, Suparna; Yoshimura, Fayth K (2004) Mink epithelial cell killing by pathogenic murine leukemia viruses involves endoplasmic reticulum stress. J Virol 78:12071-4
Nanua, Suparna; Yoshimura, Fayth K (2004) Differential cell killing by lymphomagenic murine leukemia viruses occurs independently of p53 activation and mitochondrial damage. J Virol 78:5088-96
Yoshimura, F K; Wang, T (2001) Role of the LTR region between the enhancer and promoter in mink cell focus-forming murine leukemia virus pathogenesis. Virology 283:121-31
Yoshimura, F K; Wang, T; Nanua, S (2001) Mink cell focus-forming murine leukemia virus killing of mink cells involves apoptosis and superinfection. J Virol 75:6007-15
Yoshimura, F K; Wang, T; Yu, F et al. (2000) Mink cell focus-forming murine leukemia virus infection induces apoptosis of thymic lymphocytes. J Virol 74:8119-26
Yoshimura, F K; Wang, T; Cankovic, M (1999) Sequences between the enhancer and promoter in the long terminal repeat affect murine leukemia virus pathogenicity and replication in the thymus. J Virol 73:4890-8
Chen, H; Yoshimura, F K (1998) Spacing between the enhancer and promoter of the long terminal repeat of a murine leukaemia retrovirus is required for transcriptional activation in T cells. J Gen Virol 79 ( Pt 5):1101-4

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